Project Summary Respiratory Syncytial Virus (RSV) is the leading cause of viral death in infants and young children, and a major cause of respiratory illness in immune compromised adults and the elderly. Unfortunately, there is currently no vaccine or effective therapy available for RSV. Synagis, a monthly intramuscular injection of the monoclonal antibody (mAb) palivizumab, is the only FDA-approved intervention given to a very small subset of high-risk infants as immunoprophylaxis. However, it is not effective at treating RSV. Thus, for the tens of thousands of infants hospitalized for RSV, only supportive therapy is available, and morbidity and mortality are substantial. Interestingly, RSV spreads in the lung via shedding of virus exclusively into the airway; thus, RSV must traverse airway mucus (AM) before infecting neighboring cells, and RSV remains primarily restricted to the airways with little to no systemic viremia. We believe an RSV-specific, safe, effective and topically- delivered antiviral would provide a powerful option addressing the current gap in pharmacological interventions. Mucommune is developing MM-002 to meet this goal, based on a proprietary ?muco-trapping? mAb technology platform with core claims covered by an issued US patent and exclusively licensed from UNC. MM-002 is a topical mAb treatment based on (i) reformulating RSV-binding mAb with elevated expression of a fully human Fc glycosylation that enhances its ability to trap RSV in AM, which quickly purges the virus from the airways via natural mucociliary clearance mechanisms, and (ii) stably delivering it to the lung airways using a vibrating mesh nebulizer. By concentrating an optimized mAb at the site of infection rather than delivering it systemically, we expect to enable efficacious and cost-effective treatment of RSV, with little risk of adverse side effects due to limited systemic adsorption from pulmonary delivery. In pilot studies, we showed that reformulated RSV-binding mAb can potently immobilize RSV in fresh human AM, and that intranasal delivery of muco-trapping mAb facilitated rapid elimination of RSV from the mouse lung. We just completed a RSV- infected neonatal lamb study, a highly relevant model for pediatric RSV, showing that nebulized MM-002 reduced infectious RSV viral load in infected neonatal lambs in lung homogenates and BALF down to almost non-detectible levels. Building off this promising result, we seek to develop a Master Cell Bank'ed, stable CHO cell line for high yield production of MM-002 (Aim 1), optimize the nebulization formulation and characterize delivery performance in an in vitro pediatric lung model (Aim 2), and perform rigorous dose finding studies to determine the optimal MM-002 dosing in the RSV-infected neonatal lamb model, which would impact design of subsequent GLP tox and Phase I/II clinical trial design (Aim 3). All three aims are all part of the critical path to quickly advance MM-002 into clinical development, and puts us in a position to complete IND-enabling studies and file IND within 12 months from completing this project. Our work will also help pave the way for improved, molecularly-targeted aerosolized therapies against various respiratory infections.